instructions): T cell immune responses are governed by multiple factors expressed on the cell surface, including antigen receptors, costimulatory proteins, and inhibitory molecules. In addition, interactions with antigen-presenting cells of a certain status (e.g., quiescent or activated dendritic cells) mediate the activities of T cells. The major goal of this proposal is to understand how T cell responses are regulated by mechanisms that are intrinsic or extrinsic to the cells themselves. During the current funding period, we have shown that TRAPS acts as a T cell receptor-dependent negative regulator of T cell responses. We have demonstrated that this protein regulates the induction of T cell anergy and T helper cell differentiation. These results show that TRAF6 has previously unrecognized, cell-intrinsic functions in T lymphocytes to govern multiple aspects of T cell fate. Therefore, we propose to extend our studies of the roles of TRAF6 in T cells by pursuing the following aims: (i) determine the molecular mechanisms leading to the impaired induction of T cell anergy observed in TRAF6-deficient CD4* T cells; (ii) determine the effects of T cell-specific TRAF6 deficiency on T cell differentiation; and (iii) examine how TRAF6-deficient dendritic cells affect T cell immune responses in vivo. We believe the third goal is a logical extension of this work because TRAF6 is a key signal transducer for CD40 and IL-1/Toll-like receptors. The proposed studies should help to elucidate how T cell responses are controlled at the molecular and cellular level. Such studies will provide the basis for novel therapeutic strategies for various autoimmune diseases and new methods to control T cell immune responses during chronic inflammation. RELEVANCE (See instructions): Proper immune responses are necessary to control pathogenic infections. It is equally important to limit immunological responses properly so that they do not cause chronic inflammation or autoimmune diseases. Thus, understanding molecular and cellular pathways that properly control immune responses will provide the foundation for novel intervention strategies to treat various chronic inflammatory diseases.